Mycophenolate mofetil and tacrolimus: new therapeutic options in neuroimmunological diseases

Mycophenolate mofetil (MMF) and tacrolimus are novel immunosuppressive drugs, both first established in transplantation medicine and now used increasingly in neuroimmunological diseases including myasthenia gravis, dysimmune polyneuropathies, and myositis. In myasthenia gravis, the efficacy and safety of MMF has been shown by one open-label trial; one small, double-blind, placebo-controlled trial; and a few retrospective analyses. Similarly, for tacrolimus the greatest experience and evidence for efficacy and safety have been gathered in myasthenia gravis. MMF and tacrolimus have both been used as an alternative treatment for various other autoimmune diseases in which azathioprine or cyclosporine were not sufficiently effective. However, experience with tacrolimus in dysimmune polyneuropathies and myositis is limited. At this time, the available data suggest that MMF and tacrolimus are well suited for long-term immunosuppression in patients with myasthenia gravis. The spectrum of neuroimmunological diseases in which these drugs may be used has not been finally delineated and will require further controlled studies.     

Diagnosis of peripheral neuropathies: age, sex, and occupation in relation to etiology]

The etiology of 209 cases of peripheral neuropathies was studied taking into account the most affected age ranges, as well as the sex and occupation of the patients. The age ranges of our patients for the polyneuropathies consequent to alcoholism, for diabetic polyneuropathy, for Guillain-Barré syndrome and for hereditary sensorimotor neuropathies were 20 to 50 years, 10 to 70 years and 0 to 30 years. The age range of patients with leprosy and nerve injury was 20 to 50 years, and more frequently up to 30 years. Alcoholic and diabetic polyneuropathies predominantly affected males, whereas injury to the median polyneuropathies affected laborers. Inactivity was reported by 1/3 of the patients with diabetic polyneuropathies, by 25% of the patients with polyneuropathies consequent to alcoholism and by 24% of the patients with undefined polyneuropathies.     

The spectrum of polyneuropathies in childhood detected with electromyography

Only a few studies have been reported describing polyneuropathies in a series of children. To study the clinical and neurophysiological spectrum of polyneuropathies in a large series of children and obtain an overview of their etiologies, this retrospective study reevaluated all electromyograms and electrophysiologic studies performed between 1995 and 2004 in children under 17 years of age at the Radboud University Nijmegen Medical Center, a tertiary neuromuscular reference center. Electromyograms revealing polyneuropathy were selected for further analysis (n = 118), and the medical records were reviewed to supplement electromyographic findings with the clinical diagnosis. Hereditary polyneuropathies made up 68% of the total, and 54% of these were isolated polyneuropathies; in the remaining 46%, polyneuropathy was part of a more complex disorder. The acquired polyneuropathies were primarily inflammatory. Nerve biopsies had been performed in 22 of the 118 cases (19%) and led to a diagnosis in 4 cases. Despite sophisticated investigation, 11 cases (9%) remained unclassified for underlying cause. Hereditary motor and sensory neuropathies are the most common type of polyneuropathy in childhood, followed by polyneuropathies as part of an inborn error of metabolism and inflammatory polyneuropathies (in patients in whom electromyography was used to diagnose the neuropathy). In the full series of patients, nerve biopsy did not play a prominent role in the diagnostic work-up of childhood polyneuropathies, due to the increasing availability of other laboratory (genetic and metabolic) diagnostic tools. Nerve biopsy nonetheless proved to have an important diagnostic yield in selected, complex cases.     

Correlations of nerve conduction measures in axonal and demyelinating polyneuropathies.

OBJECTIVE: In a considerable proportion of patients with polyneuropathy the electrophysiological distinction between primarily demyelinating or axonal pathology is not straightforward. This study aimed at determining whether the relation between the sensory nerve action potential (SNAP)/compound muscle action potential (CMAP) amplitude and conduction velocity (CV) or distal motor latency (DML) in demyelinating versus axonal polyneuropathy could be helpful in distinguishing these two pathophysiologies. METHODS: The relation between amplitude reduction and conduction slowing was performed using regression analysis in nerve conduction studies from 53 axonal polyneuropathies and 45 demyelinating polyneuropathies. Sensory nerve conduction studies were performed using the near-nerve needle technique. Finally, needle EMG findings in 31 muscles in axonal and in 22 muscles in demyelinating polyneuropathies were compared. RESULTS: A linear correlation between action potential amplitude and CV was seen in the majority of nerves in both axonal and demyelinating polyneuropathies. Further, an inverse linear correlation between CMAP amplitude and DML was found in most of the nerves in axonal polyneuropathies. The incidence and degree of abnormality, including decrease in action potential amplitude, was more pronounced in demyelinating than in axonal polyneuropathies, while there was no difference in EMG findings. CONCLUSIONS: Amplitude reduction and conduction slowing were correlated in axonal as well as demyelinating polyneuropathies, and a significant reduction in SNAP and CMAP amplitudes was found in demyelinating as well as axonal polyneuropathies. The correlation in axonal polyneuropathies can be attributed to a concomitant or selective loss of large, fast conducting fibers, whereas the correlation in demyelinating polyneuropathies may be explained by temporal dispersion or secondary axonal degeneration. SIGNIFICANCE: At present, relation between amplitude reduction and conduction slowing does not seem to be useful in revealing the primary pathophysiology of a polyneuropathy. Decrease in CV, increase in DML, increase in F-wave latency, conduction block and temporal dispersion should mainly be considered. Decrease in amplitude must be interpreted with caution.     

Differential diagnosis of chronic dysimmune demyelinating polyneuropathies with and without anti-MAG antibodies

The distinction between chronic demyelinating polyneuropathies associated with IgM paraproteinemia and anti-myelin-associated glycoprotein (MAG) antibodies (MAG-PN) and chronic inflammatory demyelinating polyneuropathies (CIDPs) relies on the anti-MAG antibodies assay. The aim of the study was to identify clinical and electrophysiological features suggesting a diagnosis of MAG-PN. Fourteen patients with MAG-PN and 35 with CIDP were included, and a discriminant analysis was performed to identify the clinical and electrophysiological features suggestive of MAG-PN. Pure sensory clinical phenotype, low median and ulnar terminal latency index, and absence of M responses in the lower limbs were significantly associated with the diagnosis of MAG-PN, and indicate a moderate to large increase in probability of this diagnosis in patients with chronic dysimmune demyelinating polyneuropathies.     

Inflammatory demyelinating lesions in two patients with IgM monoclonal gammopathy and polyneuropathy

We report two patients with polyneuropathy and IgM monoclonal gammopathy in whom peripheral nerve biopsy showed the widening of myelin lamellae which is characteristic of IgM paraproteinaemic neuropathy. Moreover, certain myelinated fibres were invaded by histiocytes overloaded with myelin debris, and in some instances elongated macrophage processes could be seen peeling away the myelin lamellae. The latter ultrastructural features are characteristic of inflammatory demyelinating polyneuropathies in both human and experimental pathology. Such an association has not been reported to date in human pathology, but could explain the prevalence of inflammatory demyelinating lesions in experimental models of IgM paraproteinaemic neuropathy. These two cases seem to bridge the gap between inflammatory demyelinating polyneuropathies and polyneuropathies associated with IgM monoclonal gammopathy.     

Elevated serum levels of tumor necrosis factor-α in Guillain-Barré syndrome

Activated T lymphocytes and macrophages play a putative role in the pathogenesis of Guillian-Barré syndrome. Both cell types secrete tumor necrosis factor-α, a cytokine that has well-recognized toxi effects on myelin, Schwann cells, and endothelial cells. We determined serum and cerebrospinal fluid concentrations of tumor necrosis factor α in 26 patients with Guillain-Barré syndrome, 27 patients with other polyneuropathies, 30 patients with neurological diseases of the central nervous system, and 14 helthy control subjects. Markedly increased serum levels were detected in 14 patients(54%) with Guillian-Barré syndrome and to a significantly lesser extent, in patients with other polyneuropathies (26%) and in neurological control subjects(23%). Tumor necrosis factor-α was not detected in the cerebrospinal fluid of patients with Guillain-Barré syndrome or other polyneuropathies. Increased serum concentrations in patients with Guillain-Barré syndrome or other polyneuropathies. Increased serum concentrations in patients with Guillain-Barré syndrome correlated directly with disease severity and these concentrations returned to normal in parallel with clinical recovery. These findings emphasize the complexity of the immune response in patients with Guillain-Barré syndrome and suggest that tumor necrosis factor-αL may be important in the pathogenesis of peripheral demylination in this disorder.     

血清抗糖脂抗体在自身免疫性多发性周围神经病中的意义

目的 :探讨抗周围神经膜表面糖脂抗体在自身免疫介导的多发性周围神经病中的临床意义。方法 :ELISA法测定格林 巴利综合征和慢性炎性脱髓鞘性周围神经病患者血清中抗硫脂抗体和 7种节苷脂抗体 (GM1、GM2、GA1、GD1a、GD1b、GT1b和GQ1b)的阳性率。结果 :GBS和CIDP组患者抗硫脂抗体、抗GM1、GA1和GD1b抗体的阳性率显著高于非自身免疫性周围神经病组 (P <0 0 5 ) ;此两组患者间的抗体阳性率比较则无显著差异 ;GBS组内有眼 /咽肌麻痹的患者 (17例 )与无眼肌和 (或 )咽喉肌麻痹患者 (2 5例 )的节苷脂抗体阳性率也无显著差异。结论 :血清抗硫脂抗体和抗GM1抗体增高对自身免疫介导的多发性周围神经病患者有一定临床意义。     

Prognostic value of neurofilament light in blood in patients with polyneuropathy: A systematic review

Neurofilament light protein (NfL) is a part of the neuronal skeleton, primarily expressed in axons, and is released when nerves are damaged. NfL has been found to be a potential diagnostic biomarker in different types of polyneuropathies. However, whether NfL levels can be used as a predictor for the risk of disease progression is currently less understood. We searched MEDLINE (PubMed), Embase, Cochrane Library, and Web of Science Searches and included longitudinal studies with a baseline and follow-up examination of adult patients with polyneuropathy and NfL measured in blood. Twenty studies investigating NfL as a predictor of disease progression were identified, examining eight polyneuropathy subtypes. The results from studies in Chronic Inflammatory Demyelinating Polyneuropathy (CIDP) patients were divergent, with two out of five studies finding a significant association between NfL levels and clinical outcomes. Meta-analysis of the three Guillian-Barré Syndrome (GBS) studies found higher odds for the inability to run after 1 year in patients with high levels of NfL (odds ratio 2.18, 95% confidence interval 1.04–4.56). Results from studies examining other subacute or chronic polyneuropathies like Charcot–Marie–Tooth (CMT) varied in study design and results. Our findings suggest NfL can be used as a predictor of disease progression, particularly in polyneuropathies such as CIDP and GBS. However, NfL may not serve as a reliable and cost-effective biomarker for slowly progressive polyneuropathies like CMT. Future standardized studies considering NfL as a prognostic blood biomarker in patients with different types of polyneuropathies are warranted.     

Differential diagnosis, pathogenesis and therapy of alcoholic polyneuropathy

The most common forms of polyneuropathies are the alcoholic and diabetic polyneuropathies. They each constitute 1/3 of all polyneuropathies. The first symptoms shown by the alcoholic polyneuropathy are symmetric sensory disturbances with loss of tendon reflexes and of vibration sense in the peripheral segments of the lower extremities. At the beginning one almost always finds pressure pain in the calves. Important differential clues in diagnosis compared to the diabetic neuropathy, are the age at which the disease begins, the degree to which the autonomic nerve fibres and the cranial nerves are affected, as well as the form of manifestation. Pathogenetically, a direct toxic alcohol effect can above all be suspected in accordance with the typical electrodiagnostic findings with a neurogenic pattern in the EMG in the case of normal or slightly diminished conduction velocity, and in agreement with the morphological finding of an axonal degeneration in most of the biopsies. Possibly, in a small number of cases a vitamin deficiency or a malabsorption can play a causal role. The prognosis is good by complete abstinence from alcohol.     

High resolution sonography in the evaluation of the peripheral nervous system in polyneuropathy – a review of the literature

Clinical, laboratory and electrodiagnostic studies are the mainstay in the diagnosis of polyneuropathy. An accurate etiological diagnosis is of paramount importance to provide the appropriate treatment, prognosis and genetic counselling. High resolution sonography of the peripheral nervous system allows nerves to be readily visualized and to assess their morphology. Ultrasonography has brought pathophysiological insights and substantially added to diagnostic accuracy and treatment decisions amongst mononeuropathies. In this study the literature on its clinical application in polyneuropathy is reviewed. Several polyneuropathies have been studied by means of ultrasound: Charcot–Marie–Tooth, hereditary neuropathy with liability to pressure palsies, chronic inflammatory demyelinating polyneuropathy, Guillain‐Barré syndrome, multifocal motor neuropathy, paraneoplastic polyneuropathy, leprosy and diabetic neuropathy. The most prominent reported pathological changes were nerve enlargement, increased hypo‐echogenicity and increased intraneural vascularization. Sonography revealed intriguingly different patterns of nerve enlargement between inflammatory neuropathies and axonal and inherited polyneuropathies. However, many studies concerned case reports or case series and showed methodological shortcomings. Further prospective studies with standardized protocols for nerve sonography and clinical and electrodiagnostic testing are needed to determine the role of nerve sonography in inherited and acquired polyneuropathies.     

Chronic polyneuropathies in Vest-Agder, Norway

Epidemiological data on chronic polyneuropathies, especially inflammatory types, is limited. The purpose of this study was to examine the spectrum of causes and estimated prevalence of various polyneuropathy types in Vest‐Agder, and to examine the clinical features of the Vest‐Agder population of chronic inflammatory demyelinating polyneuropathy (CIDP). In Vest‐Agder county (population of 155 464), polyneuropathy patients are registered in a database and followed prospectively. We did a measure of the database on October 31 1999. A total of 192 patients were registered. The prevalence for chronic inflammatory demyelinating polyneuropathy (CIDP) was 7.7 per 100 000 population. The course was relapsing in five of fifteen patients, progressive in four patients and slowly progressive in six of fifteen patients. Two of the fifteen patients had pure sensory symptoms. The mean Rankin disability score was 3.4 at maximal deficit and 2.1 at last follow‐up. The prevalence of paraproteinemic polyneuropathy was 5.1 per 100 000 population. None of the patients with paraproteinemic polyneuropathy were worse than slightly disabled (disability score ≤ 2). The prevalences for other polyneuropathies were as follows: polyneuropathy and RA, 1.3; polyneuropathy and Sjögren's syndrome or sicca complex, 4.5 (polyneuropathy was the presenting symptom in five of seven patients); sarcoidosis 1.9; polyneuropathy and chronic Lyme, 0.6; paraneoplastic polyneuropathy, 1.9; diabetic polyneuropathy 23.2; vitamin deficiency, 5.1; alcoholic and toxic polyneuropathy, 19.9; hereditary polyneuropathy, 14.8. Cryptogenic polyneuropathies made up 26% of all polyneuropathies. The mean disability score was 2.0 (SD 1.1). In conclusion, prevalence of CIDP was significantly higher than previously reported, and the prognosis was good in the majority of patients. Patients with paraproteinemic polyneuropathy were not severely disabled. Polyneuropathy was the presenting symptom in the majority of patients with Sjögren's syndrome or sicca complex.     

Diagnosis of chronic neuropathy

Chronic neuropathy is the most frequent condition affecting the peripheral nervous system. It includes symmetrical polyneuropathies, multifocal mononeuropathies, mononeuropathies and radiculopathies. Mononeuropathies are mainly due to compression or entrapment and are not discussed in this review, which focuses on polyneuropathies and multifocal mononeuropathies with a chronic course, lasting for more than 2 months. Their diagnosis requires a systematic approach including clinical, electrophysiological, biological, and sometimes pathological investigations. The search for an etiological diagnosis may involve a very wide panel of hereditary and acquired diseases. Despite progress in the understanding and diagnosis of many chronic neuropathies, some of them remain unresolved. Received: 19 June 1998 Accepted: 27 June 1998     

Fampridine‐PR (prolonged released 4‐aminopyridine) is not effective in patients with inflammatory demyelination of the peripheral nervous system

Fampridine‐PR is a voltage‐gated potassium channel inhibitor potentially improving nerve conduction in demyelinated axons. Based on its established clinical efficacy in patients with demyelination in the central nervous system, we assessed if fampridine‐PR is also effective in patients with inflammatory demyelination of the peripheral nerve. In this small open‐label study, 10 patients with chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) were treated with fampridine‐PR 10 mg BID for 28 days and assessed clinically as well as by nerve conduction studies. In this study, Fampridine‐PR failed to improve CIDP based on clinical measures and nerve conduction studies. Our findings suggest that Fampridine‐PR appears to be ineffective in demyelinating polyneuropathies. These observations may indicate a more complex mode of action beyond improving action potential conduction in demyelinated axons.     

Electrophysiology in demyelinating polyneuropathies

Demyelinating neuropathies are disorders of the peripheral nervous system in which the myelin sheath of axons is affected by immune-mediated or genetically determined processes. In single axons, demyelination yields conduction block due to extinction of action potentials or conduction slowing. Motor nerve conduction studies assess these phenomena in nerves, which consist of many axons. It is important to distinguish demyelinating from axonal polyneuropathies as this allows accurate diagnosis and institution of appropriate treatment. Immunological treatment in acquired demyelinating polyneuropathies is often successful. Criteria were developed for motor conduction velocity slowing and for conduction block, which assume demyelination if the findings cannot be explained by axon loss. Criteria-sets for the diagnosis of specific polyneuropathies require that several variables are consistent with demyelination in several nerves. However, these sets are based on expert opinion and have a low sensitivity such that treatable neuropathies may be underdiagnosed. Evidence-based sets are currently being developed. Axon loss is the main determinant of the clinical deficit in demyelinating neuropathies and, if its mechanisms are further elucidated, it may be prevented by pharmacological treatment. Excitability testing, which assesses axonal membrane potential and ion-channel activities, may reveal some of these mechanisms.     

Intravenous immunoglobulin therapy for neuromuscular disorders

Treatment of specific immune-mediated neuromuscular disorders involves consideration of many factors including severity of illness, concurrent medical problems, supportive therapies, and immune-modulating therapies. Many immune-modulating therapies are available, including steroids, an increasing number of immunosuppressive drugs, plasmapheresis, and intravenous immunoglobulin (IVIG). Deciding on which immune-modulating therapy involves selecting from those with proven efficacy for a specific disorder and global considerations of which therapies are most appropriate for an individual patient's circumstances. IVIG has become a commonly used therapy as it is well tolerated, easily administered, and is often efficacious with a relatively rapid action. IVIG has become a first-line therapy for several immune-mediated demyelinating polyneuropathies and may play a role in treating exacerbations of myasthenia gravis and selected chronic treatment-refractory cases of Lambert-Eaton myasthenic syndrome, dermatomyositis, and polymyositis.     

Immune neuropathies

Immunoneuropathies constitute but a small percentage of polyneuropathies, compared to metabolic or toxic neuropathies. However, refined techniques of immunochemistry and biopsy have increasingly improved the etiological characterisation of immunoneuropathies. This review deals with the present diagnostic tools for investigation of polyneuropathies in general and with special immunological means of diagnosis. After two short case reports from our department, the main groups of peripheral nerve diseases, in which immunologic pathomechanisms are postulated, are described regarding symptomatology, special diagnostics and therapy. These groups of diseases are listed with respect to scientific evidence of their immunologic etiology, ranging from acute and chronic Guillain-Barré-Syndrome to paraneoplastic and neuropathies in HIV infections. The conclusion gives a summary of general pathogenetic considerations in immunoneuropathies.     

<Emphasis Type="Italic">N</Emphasis><Superscript>ε</Superscript>-Carboxymethyllysine in diabetic and non-diabetic polyneuropathies

Increased oxidative stress and advanced glycosylation are important factors in the development of diabetic neuropathy. In non-diabetic neuropathies their influence has not been investigated in detail so far. We studied the localisation of N(epsilon)-carboxymethyllysine (CML) - a biomarker for oxidative stress - by immunohistochemistry in sural nerve biopsies of 31 patients with different polyneuropathies [diabetic polyneuropathy (n=5), alcohol-associated polyneuropathy (n=4), vitamin B12-deficient polyneuropathy (n=6), chronic inflammatory demyelinating polyneuropathy (CIDP) (n=6), vasculitic neuropathy (n=6), Charcot-Marie-Tooth disease type I (CMT I) (n=4)] and 4 normal controls. CML was detected in the perineurium of patients with diabetic, alcohol-associated, vitamin B12-deficient and vasculitic polyneuropathies. Epineurial, perineurial and endoneurial vessels were CML positive in diabetic, vitamin B12-deficient and vasculitic polyneuropathies. CML was also found in mononuclear inflammatory cells in vasculitic neuropathy. In CIDP and normal controls there was only marginal perineurial CML deposition in 2/6 and 1/4 cases. In CMT I no CML was detected. Immunohistochemical results were confirmed by immunoblot. Our data suggest a role of oxidative stress in the pathogenesis not only of diabetic but also of alcohol-associated, vitamin B12-deficient and vasculitic polyneuropathies. It may be a minor pathogenetic factor in CIDP and may not be involved in CMT I. Underlying causes for increased oxidative stress may be an elevated production of reactive oxygen species and an impairment of antioxidative defences. Therefore, an antioxidative treatment should be considered in alcohol-associated, vitamin B12-deficient and vasculitic polyneuropathy.